Abstract
Background
The National Cancer Institute Working Group (NCI-WG 96) guidelines classified individuals having a B-cell clone with CLL immunophenotype as CLL if the absolute lymphocyte count (ALC) was ≥5 × 109/L. 2008 International Workshop on CLL guidelines (IWCLL 2008) classified as CLL if the absolute B-cell count is ≥5 × 109/L or as monoclonal B-cell lymphocytosis (MBL) if the absolute B-cell count is <5 × 109/L. This study of Olmsted County, Minnesota, assessed effects of these changes on incidence rates and presentation from 2000–2010.
Methods
Using diagnostic indices available through the Rochester Epidemiology Project and the Mayo CLL database, we identified all newly diagnosed CLL and high count MBL cases from 2000–2010. Age and sex specific incidence rates were determined.
Results
With NCI-WG 96 criteria, there were 115 cases of CLL and 8 cases of MBL. Using IWCLL 2008 classification, there were 79 cases of CLL and 40 cases of MBL. Rai stage distribution (low, intermediate, high) using NCI-WG 96 was 60.9%, 33.9% and 5.2% compared to 43.0%, 49.4%, and 7.6% under IWCLL 2008 criteria. The age- and sex-adjusted incidence rate (per 100,000) for CLL and MBL were 10.0 and 0.66 using NCI-WG 96 versus 6.8 and 3.5 using IWCLL 2008. Median time to treatment (TTT) using NCI-WG 96 was 9.2 years versus 6.5 years with IWCLL 2008
Conclusions
Use of the IWCLL 2008 guidelines reduce the incidence of CLL, alter the distribution of initial Rai stage at diagnosis and shorten median TTT.
Keywords: Chronic lymphocytic leukemia, monoclonal B-cell lymphocytosis, incidence, epidemiology, natural history
INTRODUCTION
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is the most prevalent adult lymphoid malignancy in the United States. Prior population-based studies of leukemia incidence in Olmsted County, located in southeastern Minnesota, have provided accurate and long term information on disease incidence.1–4 Comparisons of CLL incidence patterns in Olmsted County from 1935 to 1989 showed an increase that was likely related to earlier diagnosis associated with the introduction of automated hematology analyzers and improved access to health care for older adults.2
With subsequent improved sensitivity of flow cytometry techniques, the ability to accurately detect small circulating B-cell clones in screening studies of the general population has been described.5,6 Such studies suggest that approximately 4% of adults over the age of 40 have detectable clonal B-cell populations with an immunophenotype consistent with CLL, referred to as low count monoclonal B-cell lymphocytosis (MBL).5,7 In addition to population screening studies, there are a substantial number of patients who are identified to have borderline or mildly elevated lymphocyte counts on routine clinically obtained automated complete blood counts. This high count MBL is detected when a clonal B-cell population is identified during the evaluation of such patients via flow cytometry, yet does not meet the diagnostic criteria for CLL. The majority of these express CLL immunophenotype, but a small percent may type as other low grade lymphoproliferative disorders. 5,7
Population screening studies for low count MBL have been reported, and the risk of progression to CLL is low.8,9 High count MBL has been associated with a risk of progression to CLL requiring treatment of approximately 1% per year.5,9 Molecular markers, such as CD 38 expression, may be associated with outcome in high count MBL.10
The classification criteria for CLL have changed several times in the last 25 years. Prior to 2008, the diagnosis of CLL was based on the National Cancer Institute sponsored Working Group guidelines (NCI-WG 96) which classified individuals having a B-cell clone with characteristic immunophenotype as CLL if the absolute lymphocyte count(ALC) was ≥5 × 109/L.11 The updated 2008 International Workshop on CLL Guidelines (IWCLL 2008) classified individuals having a characteristic immunophenotype as CLL if the absolute B-cell count is ≥5 × 109/L.12 Individuals with clonal B-cell populations with an absolute B-cell count <5 × 109/L and no associated adenopathy, splenomegaly or cytopenias are classified as MBL. 12 Recent estimates suggest that this reclassifies approximately 30% of cases that were previously termed Rai stage 0 CLL to MBL.7,13–15
To assess the impact of these changes on the incidence patterns, presentation, and clinical outcome of CLL and high count MBL, we conducted an incidence study of CLL and MBL in Olmsted County, Minnesota, for the years 2000–2010.
METHODS
Olmsted County is located in southeastern Minnesota and is unique as the medical records of virtually all persons living in the county (irrespective of whether they are Mayo Clinic patients) have been archived, linked and made accessible for approved research projects. This resource is termed the Rochester Epidemiology Project (REP).16,17 This research was approved by the Mayo Clinic Institutional Review Board (IRB), the Olmsted Medical Center IRB, and the REP. The Mayo Clinic CLL database includes all patients with a diagnosis of CLL seen in the Division of Hematology at Mayo Clinic since 1995 who permit their records to be used for research purposes.13,18 Baseline demographic and clinical factors (including age, sex, Rai stage, Eastern Co-operative Oncology Group (ECOG) performance status, complete blood count (CBC), absolute lymphocyte count (ALC), beta-2 microglobulin (β2M), IGHV status, cytogenetic abnormalities detected by interphase fluorescent in situ hybridization (FISH), and expression of ZAP-70, CD49d and CD38) are abstracted from clinical and research records on all patients and maintained on a prospective basis. Time from initial diagnosis, treatment history, disease-related complications, time to first treatment (TTT) and survival are also recorded. 18 Using diagnostic indices available through the REP, Mayo CLL database and Mayo Clinic hematopathology records, we identified all newly diagnosed CLL and high count MBL cases in Olmsted County from 2000–2010. High count MBL cases were included if they expressed a CLL immunophenotype. All charts that were not already included in the Mayo CLL database were manually abstracted. Incidence rates and demographics were classified by both the NCI-WG 96 guidelines and the IWCLL 2008 guidelines with then compared.8,9 Denominator age- and sex-specific person-years for incidence rates were estimated from US decennial census data for Olmsted County. The population of Olmsted County in 2010 was 144,248.19 Incidence rates were age- and sex-adjusted to the 2010 US white population. TTT was estimated using the Kaplan-Meier method. All analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC, USA).
RESULTS
There were a total of 123 incident cases (either MBL or CLL) having a clonal B-cell population of CLL phenotype among Olmsted County residents between 2000–2010. Three of these cases had both an MBL and a subsequent CLL diagnosis during the time period of interest. All incident cases were classified using both the NCI-WG 96 criteria and the IWCLL 2008 classifications. When classified by the NCI-WG 96 criteria, there were 115 cases of CLL and 8 MBL cases. Using the IWCLL 2008 criteria, there were 79 cases of CLL and 40 cases of MBL. Four cases of CLL, using the NCI-WG 96 guidelines, were re-classified as MBL under IWCLL 2008 guidelines and subsequently were excluded from our reported IWCLL 2008 cohort since the date of revised MBL diagnosis now fell prior to 2000. (Figure 1) Median age at diagnosis was 71.7 years for CLL and 74.6 years for MBL using NCI-WG 96 compared to 73.7 and 71.5 under IWCLL 2008 criteria. Using NCI-WG 96 criteria, median ALC at diagnosis was 7.6 × 109/L for CLL and 3.3 × 109/L for MBL while median absolute B-cell count was 4.6 × 109/L and 1.4 × 109/L for CLL and MBL respectively. Under IWCLL 2008 criteria, median ALC at diagnosis was 8.1 × 109/L for CLL and 5.9 × 109/L for MBL while median absolute B-cell count was 7.1 × 109/L and 2.8 × 109/L for CLL and MBL respectively (Tables 1 and 2).
Figure 1.
Differences in CLL or High Count MBL classification based on criteria used
Table 1.
Characteristics of Olmsted County, Minnesota, residents with newly diagnosed CLL in 2000–2010, shown for each diagnostic criteria applied. Continuous variables are summarized as median (range); categorical variables are summarized as N (%).
| 1996 Criteria | 2008 Criteria | |||
|---|---|---|---|---|
| N | N | |||
| Sex | 115 | 79 | ||
| Male | 66 (57.4) | 49 (62.0) | ||
| Female | 49 (42.6) | 30 (38.0) | ||
| Age at diagnosis, year | 115 | 71.7 (46.9 – 92.9) | 79 | 73.7 (47.4 – 92.9) |
| ALC (× 109/L) | 114 | 7.6 (1.0 – 98.1) | 78 | 8.1 (1.0 – 98.1) |
| B-cell count (× 109/L) | 105 | 4.6 (0.1 – 93.5) | 69 | 7.1 (0.1 – 93.5) |
Table 2.
Characteristics of Olmsted County, Minnesota, residents with high count MBL in 2000–2010 shown for each diagnostic criteria applied. Continuous variables are summarized as median (range); categorical variables are summarized as N (%).
| 1996 Criteria | 2008 Criteria | |||
|---|---|---|---|---|
| N | N | |||
| Sex | 8 | 40 | ||
| Male | 5 (62.5) | 20 (50.0) | ||
| Female | 3 (37.5) | 20 (50.0) | ||
| Age at diagnosis, year | 8 | 74.6 (47.7 – 88.9) | 40 | 71.5 (47.7 – 88.9) |
| ALC (× 109/L) | 7 | 3.3 (2.1 – 4.2) | 39 | 5.9 (2.1 – 15.6) |
| B-cell count (× 109/L) | 4* | 1.4 (0.6 – 2.1) | 36 | 2.8 (0.6 – 4.9) |
Of the four people with missing B cell count, all had an ALC of <5 × 109/L as determined by the clinical or hematopathology laboratories.
The distribution of Rai stage at diagnosis of the CLL cases also varied under the two different classifications. Using the NCI-WG 96 criteria, 60.9%, 33.9%, and 5.2% were Rai stage 0, I–II, and III–IV, respectively, as compared to 43.0%, 49.4%, and 7.6% under the IWCLL 2008 criteria. In contrast to the shift toward more advanced stage at diagnosis under the IWCLL 2008 criteria, the distribution of biologic prognostic parameters (CD38, ZAP-70 and FISH) appeared to be similar under the two criteria (Table 3). Since the majority of the incidence cases were early stage and diagnosed in primary care settings, greater than 50% of the cases did not have a beta2-microglobulin within 6 months of diagnosis or a mutation status available.
Table 3.
Prognostic profile of Olmsted County, Minnesota, residents with newly diagnosed CLL in 2000–2010, shown for each diagnostic criteria applied. Percentages are calculated using subjects with non-missing values.
| 1996 Criteria N (%) | 2008 Criteria N (%) | |
|---|---|---|
| Stage | ||
| Rai 0 | 70 (60.9) | 34 (43.0) |
| Rai I–II | 39 (33.9) | 39 (49.4) |
| Rai III–IV | 6 (5.2) | 6 (7.6) |
| CD38+ | 29 (28.4) | 21 (30.9) |
| Missing | 13 | 11 |
| ZAP-70+ | 25 (36.2) | 19 (40.4) |
| Missing | 46 | 32 |
| FISH | ||
| Del13q14 | 38 (45.2) | 24 (41.4) |
| No defects detected | 20 (23.8) | 16 (27.6) |
| Trisomy 12 | 17 (20.2) | 12 (20.7) |
| Del11q23 | 7 (8.3) | 4 (6.9) |
| Del17p13 | 2 (2.4) | 2 (3.4) |
| Missing | 31 | 21 |
After age- and sex-adjustment to the 2010 US White population, the incidence rate of CLL in Olmsted County in our last published study for the period 1985 to 1989 was 9.8 per 100,000.1,2 For 2000–2010, the age- and sex-adjusted incidence rates (per 100,000) for CLL and high count MBL in Olmsted County were 10.0 and 0.66 using the NCI-WG 96 criteria and 6.8 and 3.5 using the IWCLL 2008 criteria.
The estimated median time to first treatment (TTT) for cases of newly diagnosed CLL as defined by NCI-WG 96 was 9.2 years compared to 6.5 years by IWCLL 2008 criteria (Figure 2a). The comparison of TTT between the two classification guidelines for Rai 0 CLL is shown in Figure 2b.
Figure 2.
Figure 2a: Time to First Treatment for CLL (All stages) 2000–2010
Figure 2b: Time to first treatment comparison for CLL (Rai stage 0) 2000–2010
DISCUSSION
This population-based study provides a number of important insights regarding the prevalence of CLL and high count MBL. First, although the incidence rate of CLL increased between 1935–1989,1,2 there has been no further increase in the incidence of CLL over 2000–2010 when evaluated using the same diagnostic criteria. This observation is consistent with the hypothesis that the previous increase was largely due to an increase in ascertainment due to more widespread use of automated blood counters and flow cytometry rather than a true change in the incidence of the disease. Second, the study illustrates how the 2008 revisions to the CLL diagnostic guidelines have had a profound impact on the incidence of CLL. By basing the criteria on an absolute B-cell count of ≥5 × 109/L rather than an ALC of ≥5 × 109/L, these criteria have reduced the incidence of CLL by ~33% (10.0/100,000 to 6.8/100,000). Third, this is the first population-based study to accurately define the incidence of clinically ascertained high count MBL.
In addition to these important effects on disease incidence, the revisions have also had substantial effects on the distribution of disease stage at diagnosis and median time from diagnosis to first treatment. These alterations in natural history due to revisions to the diagnostic criteria have important implications for patient counseling and provide important contextual information for interpreting future epidemiologic studies and trials evaluating the clinical benefit of early therapeutic intervention. While some may use these data to argue against the revisions to the diagnostic criteria in the 2008 update, the available evidence, including that from this study, suggests that these changes have more firmly established the diagnosis of CLL to clinically meaningful outcomes and provided strong clinical justification for these changes10,13,15,20. Indeed a study of 459 patients from Mayo Clinic suggest that an even higher B-cell threshold (>11 × 109/L) was the best level to anchor the diagnosis to overall and treatment free survival15, a finding that was confirmed in population-based studies from Italy20.
It should be noted that the incidence rates reported are higher than the most recent report by SEER, but similar to the incidence reported from the province of Manitoba, Canada, where there is centralized flow cytometry.21,22 A similar difference in incidence rates (versus SEER) was noted in our prior study of Olmsted County, Minnesota.1,2 These differences are likely due to more complete ascertainment in Olmsted County than SEER due to both centralized flow cytometry (as in Manitoba14,15) and centralized record keeping which has also been shown to result in better ascertainment and increased incidence.23
Defining the incidence of clinically evident high count MBL will have implications for clinical practice. Evidence is emerging that that individuals with high count MBL are at risk not only for progression to CLL, but also appear to have increased susceptibility to significant infection and second cancers.24,25 Having a unique International Classification of Diseases (ICD) code for clinically identified MBL will be important in tracking and future monitoring studies. Recommendations for monitoring of individuals with high count MBL have now been published.7
In conclusion, the incidence of CLL based on the pre-2008 criteria was stable over the last 25 years. However, the changes to the CLL diagnostic guidelines made in 2008 have resulted in a reclassification of a significant percentage of patients previously considered to have CLL to high count MBL. This change in definition has had a profound impact on the epidemiological and clinical characteristics of these two entities. This change will need to be further evaluated in ongoing incidence studies of CLL and MBL and will also need to be taken into account during future epidemiological and clinical studies.
Table 4.
CLL and MBL Incidence in 2000–2010 among residents of Olmsted County, Minnesota
| High Count MBL | CLL | |||
|---|---|---|---|---|
| 1996 Criteria Rate (95% CI)* | 2008 Criteria Rate (95% CI)* | 1996 Criteria Rate (95% CI)* | 2008 Criteria Rate (95% CI)* | |
| Age adjusted | 0.65 (0.20–1.11) | 3.5 (2.4–4.6) | 9.9 (8.1–11.7) | 6.7 (5.3–8.2) |
| Age and sex adjusted | 0.66 (0.20–1.13) | 3.5 (2.4–4.6) | 10.0 (8.2–11.8) | 6.8 (5.3–8.3) |
| Age adjusted – Male | 0.95 (0.09–1.81) | 3.9 (2.2–5.7) | 13.2 (9.9–16.4) | 9.8 (7.0–12.7) |
| Age Adjusted - Female | 0.45 (0.00–0.95) | 3.3 (1.8–4.8) | 7.6 (5.5–9.8) | 4.5 (2.9–6.1) |
Incidence per 100,000 person-years directly age- or age-and sex-adjusted to the 2010 United States white population.
Acknowledgments
This study was made possible using the resources of the Rochester Epidemiology Project, which is supported by the National Institute on Aging of the National Institute of Health under Award Number R01AG034676. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Support was also provided, in part, from NIH grants CA118444 and CA95241.
Footnotes
AUTHORSHIP CONTRIBUTIONS: T.C. led the conception and design of the study, collection, analysis, and interpretation of the data and wrote the manuscript; A.N., S.S. and C.H. helped with the conception and design of the study, collection, analysis, and interpretation of the data and editing of the manuscript; S.A., K.R., N.K., C.Z., W.D., J.L., J.C., C.V., E.H. and T.S helped with the conception and design of the study, analysis, and interpretation of the data and editing of the manuscript.
CONFLICT OF INTEREST DISCLOSURE: The authors declare no competing financial interests.
References
- 1.Call TG, Noel P, Habermann TM, Beard CM, O’Fallon WM, Kurland LT. Incidence of leukemia in Olmsted County, Minnesota, 1975 through 1989. Mayo Clin Proc. 1994 Apr;69(4):315–322. doi: 10.1016/s0025-6196(12)62214-9. [DOI] [PubMed] [Google Scholar]
- 2.Call TG, Phyliky RL, Noel P, et al. Incidence of chronic lymphocytic leukemia in Olmsted County, Minnesota, 1935 through 1989, with emphasis on changes in initial stage at diagnosis. Mayo Clin Proc. 1994 Apr;69(4):323–328. doi: 10.1016/s0025-6196(12)62215-0. [DOI] [PubMed] [Google Scholar]
- 3.Kyle RA, Nobrega FT, Kurland LT, Elveback LR. The 30-year trend of leukemia in Olmsted County, Minnesota, 1935 through 1964. Mayo Clin Proc. 1968 May;43(5):342–353. [PubMed] [Google Scholar]
- 4.Linos A, Kyle RA, Elveback LR, Kurland LT. Leukemia in Olmsted County, Minnesota, 1965--1974. Mayo Clin Proc. 1978 Nov;53(11):714–718. [PubMed] [Google Scholar]
- 5.Rawstron AC, Bennett FL, O’Connor SJ, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. New Engl J Med. 2008 Aug 7;359(6):575–583. doi: 10.1056/NEJMoa075290. [DOI] [PubMed] [Google Scholar]
- 6.Rawstron AC, Green MJ, Kuzmicki A, et al. Monoclonal B lymphocytes with the characteristics of “indolent” chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood. 2002 Jul 15;100(2):635–639. doi: 10.1182/blood.v100.2.635. [DOI] [PubMed] [Google Scholar]
- 7.Shanafelt TD, Ghia P, Lanasa MC, Landgren O, Rawstron AC. Monoclonal B-cell lymphocytosis (MBL): biology, natural history and clinical management. Leukemia. 2010 Mar;24(3):512–520. doi: 10.1038/leu.2009.287. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Fazi C, Scarfo L, Pecciarini L, et al. General population low-count CLL-like MBL persists over time without clinical progression, although carrying the same cytogenetic abnormalities of CLL. Blood. 2011 Dec 15;118(25):6618–6625. doi: 10.1182/blood-2011-05-357251. [DOI] [PubMed] [Google Scholar]
- 9.Scarfo L, Fazi C, Ghia P. MBL versus CLL: how important is the distinction? Hematol Oncol Clin North Am. 2013 Apr;27(2):251–265. doi: 10.1016/j.hoc.2013.01.004. [DOI] [PubMed] [Google Scholar]
- 10.Shanafelt TD, Kay NE, Rabe KG, et al. Survival of patients with clinically identified monoclonal B-cell lymphocytosis (MBL) relative to the age- and sex-matched general population. Leukemia. 2012 Feb;26(2):373–376. doi: 10.1038/leu.2011.211. [DOI] [PubMed] [Google Scholar]
- 11.Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996 Jun 15;87(12):4990–4997. [PubMed] [Google Scholar]
- 12.Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008 Jun 15;111(12):5446–5456. doi: 10.1182/blood-2007-06-093906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Shanafelt TD, Kay NE, Rabe KG, et al. Brief report: natural history of individuals with clinically recognized monoclonal B-cell lymphocytosis compared with patients with Rai 0 chronic lymphocytic leukemia. J Clin Oncol. 2009 Aug 20;27(24):3959–3963. doi: 10.1200/JCO.2008.21.2704. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Shanafelt TD, Kay NE, Call TG, et al. MBL or CLL: which classification best categorizes the clinical course of patients with an absolute lymphocyte count >or= 5 × 10(9) L(−1) but a B-cell lymphocyte count <5 × 10(9) L(−1)? Leuk Res. 2008 Sep;32(9):1458–1461. doi: 10.1016/j.leukres.2007.11.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Shanafelt TD, Kay NE, Jenkins G, et al. B-cell count and survival: differentiating chronic lymphocytic leukemia from monoclonal B-cell lymphocytosis based on clinical outcome. Blood. 2009 Apr 30;113(18):4188–4196. doi: 10.1182/blood-2008-09-176149. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Rocca WA, Yawn BP, St Sauver JL, Grossardt BR, Melton LJ., 3rd History of the Rochester Epidemiology Project: half a century of medical records linkage in a US population. Mayo Clin Proc. 2012 Dec;87(12):1202–1213. doi: 10.1016/j.mayocp.2012.08.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.St Sauver JL, Grossardt BR, Yawn BP, Melton LJ, 3rd, Rocca WA. Use of a medical records linkage system to enumerate a dynamic population over time: the Rochester epidemiology project. Am J Epidemiol. 2011 May 1;173(9):1059–1068. doi: 10.1093/aje/kwq482. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Shanafelt TD, Rabe KG, Kay NE, et al. Age at diagnosis and the utility of prognostic testing in patients with chronic lymphocytic leukemia. Cancer. 2010 Oct 15;116(20):4777–4787. doi: 10.1002/cncr.25292. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.censusviewer.com. Census 2010 and 2000 Interactive Map, Demographics, Statistics, Graphs, Quick Facts. Minnesota: 2012. [Accessed 9/23/2013, 2012]. Population of Olmsted County. http://censusviewer.com/county/MN/Olmsted. [Google Scholar]
- 20.Molica S, Mauro FR, Giannarelli D, et al. Differentiating chronic lymphocytic leukemia from monoclonal B-lymphocytosis according to clinical outcome: on behalf of the GIMEMA chronic lymphoproliferative diseases working group. Haematologica. 2011 Feb;96(2):277–283. doi: 10.3324/haematol.2010.030189. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Nea Howlader. SEER Cancer Statistics Review, 1975–2010. [Accessed July 26, 2013];Chronic Lymphocytic Leukemia. 2013 http://seer.cancer.gov/statfacts/html/clyl.html.
- 22.Seftel MD, Demers AA, Banerji V, et al. High incidence of chronic lymphocytic leukemia (CLL) diagnosed by immunophenotyping: a population-based Canadian cohort. Leuk Res. 2009 Nov;33(11):1463–1468. doi: 10.1016/j.leukres.2009.06.013. [DOI] [PubMed] [Google Scholar]
- 23.Zent CS, Kyasa MJ, Evans R, Schichman SA. Chronic lymphocytic leukemia incidence is substantially higher than estimated from tumor registry data. Cancer. 2001 Sep 1;92(5):1325–1330. doi: 10.1002/1097-0142(20010901)92:5<1325::aid-cncr1454>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
- 24.Moreira J, Rabe KG, Cerhan JR, et al. Infectious complications among individuals with clinical monoclonal B-cell lymphocytosis (MBL): a cohort study of newly diagnosed cases compared to controls. Leukemia. 2013 Jan;27(1):136–141. doi: 10.1038/leu.2012.187. [DOI] [PubMed] [Google Scholar]
- 25.Solomon B, Rabe KG, Moreira J, Schwager S, Cerhan JR, Call TG, Kay NE, Slager SL, Shanafelt TD. Risk of Cancer in Patients with Clinical Monoclonal B-Cell Lymphocytosis (MBL): A Cohort Study of Newly Diagnosed Patients Compared to Controls. Blood (ASH Annual Meeting Abstracts) 2012;120 [Google Scholar]